The grant proposal "Complex Chemo types: Discovery, Methodology, and Library Expansion" describes a renewal application for The Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) which was initiated in 2002 with funding from the NIGMS. The three goals of Center have been to develop new reaction methodologies for the stereo controlled synthesis of complex libraries, to create a publicly accessible database of chemical protocols, and to provide chemical libraries to members of the biological community in collaborative efforts. The CMLD-BU has organized the Chemical Library Consortium (CLC) to provide members of the biology community with chemical libraries. The PI (Porco) and co-Pi's (Panek, Snyder, and Schaus) have demonstrated the ability to construct a number of complex chemical libraries in the first funding period with several members exhibiting unique bioactivities. The CMLD-BU currently maintains a collection of approximately 5000 novel compounds which have been made available to 23 collaborators in the U.S. for biological screening in a wide variety of assays. The proposed projects described in the renewal application are focused on development of new reaction processes to obtain novel molecular structures (chemo types) for biological screening. The CMLD-BU will also develop strategies, chemical methods, and micro fluidic technologies to accomplish the syntheses of small-molecule libraries. The first project, "Skeletal Diversity Employing Scaffold Rearrangements, Annulations, and Cycloadditions" will focus on the development of rearrangements, cycloadditions, and ring annulation processes for diversity-oriented synthesis. Project 2, "Discovery of Novel Transformations and Chemo types Using Reaction Screening" continues reaction screening and discovery approaches to access novel chemotypes.Project 3, "Development of Micro fluidic Technologies for Reaction Discovery, Methodology Development, and Library Synthesis" is a collaborative effort between the CMLD-BU and the laboratory of Professor Klavs Jensen of the Department of Chemical Engineering at MIT to develop enabling microfluidic technologies for multidimensional reaction screening, photochemical and microwave-mediated reactions, automated reaction optimization, and chemical synthesis of libraries. All chemical libraries and arrays will be submitted to the Molecular Libraries Small Molecular Repository and biological data uploaded to PubChem. Taken together, the proposed projects will create valuable tools to study biology and advance the role of chemistry in biomedical research.